Preparation of threonine and intermediates therefor



Patented Oct. 16, 1951 UNITED STATES PATENT OFFICE;

N Drawing: Application December'B; 1948;

Serial No. 64,424

21 Claims. 1.

Thisinvention relates to the preparation-of aminoacids from readilyavailable starting materials. More particularly, it is concerned-with a new and improved process for manufacturing DL -threonineran essential amino acid required f or growth, from a-halo-fi-alkoxy-n-butyric acids. It is also concerned with the preparation of certain-novel chemical compounds, produced as intermediates inthe synthesis of DL-threonine. These intermediate compounds amides, mono or disubstituted amides, and secondary heterocyclic amine derivatives of (ll-ahalo-e-alkoxy-n-butyric acids.

Methods now availablefor the preparation of the essential amino acid DL-threoninea're' geii- (I940), involves aminat'ing 'a racemic mixture of a-bromo-fi-methoXy-butyric acids which is approximately 40% precursor of DL-threonine and 60% precursor of DL-allothreonine. Since allothreonine is of no value, the separation of DL- threonine must be carried out. This separation is difficult and costly. The DL-threonine is isolated in the pure state in about 17.5% yield by formylation and fractional crystallization.

Similarly, the method of West et al. as disclosed in Jour. Biol.- Chem., Vol. 122', page 605 (19 38) involves utilizing one of the diastereoisomer forms of a-brcmo-,8-methoxy-n-butyric acid, having a melting point of about 62-63 C., as the starting material. While this racemic form is readily prepared; unfortunately upon amination and hydrolysis it resulted in high yields of DL-allothreonine and only traces of DL-threonine. I

Theother diastereoisomeric form of dl-abromo-B-methoxy-n-butyric acid, which melts at 49C. results in DL-threonine in good yield on amination and hydrolysis but no practical method exists for its production.

It is one of the objects of our invention to provid a method for converting the high melting racemic form of d1-a-bromo-fi-methoxy-n-butyric acid of West et al. and the racemic mixtures of Carter et to threonine which method is eflicient in its operation and'results in high yields of the desired DL-threonine.

The foregoing aims and objectives of this invention as well as others subsequently explained herein, will be apparent from the ensuing disclosure of certain preferred embodiments of our invention.

We have now discovered a procedure whereby include the I the racemic modificationsof a halo-fl-alkoxy-nbutyric acids which-normally lead to DL'allothreonine on amination-and hydrolysis can be utilized for the production of DL-threonine.

1 Regarded in certain of its broader aspects, the new process, according to our invention,- comprises first converting the dl-a-halo-B-alkoxy-nbutyric acid to dl-w-halo-flalkoxy-nbutyric acid halide by reaction with a halogenatingagent in an organic solvent medium, reacting the latter solution with ammonia, primary amines or secondary amines, recovering the amide derivative and then aminating I and hydrolyzing the amido derivative to form- DL-threonine in high-yield. It appears-that the-formation Ofthe new amido derivatives results-in am'olecular rearrangement which'is responsible-for the production of DL- threonine" rather than DL-allothreonine from thesta-rting racemate.--

' In accordance with our invention abenzene solution of dl-a-h-alo-B-alkoxym-butyric acid which normally results in the formation-of DL- allothreonine -upon amination and hydrolysis is treated with a halogenating-agent such as thionyl chloridewThe'reaction is carried outby heating the reactants to refiux temperature for approximately one 'andone-half hours. This results in formation of a benzene solutionof a halol3-all oX-yn-butyric acid halide.

After removal of sulfur dioxide and hydrogen halide, the benzene solution of a-halo-,B-alkoxybutyric acid halide is treated with ammonia or a benzene solution of a primary or "secondary amine, and a compound of the following-structure is recovered.

wherein R is an-alkyl group; X is halogen and R is NH2;- NI-I-aryl; N(a-lkyl-)z-or a secondary heterocyclicamine;

Among suitable amines may be mentioned piperidine, ammonial dimethylam'ine and aniline.

Theamido'compound-is treated with liquid ammonia, or a mixture of liquidammom'a and a lower aliphatic alcohol to form an a-aminofi-alkox y-mb'utyric acid amide. The solution is concentrated-to dryness and "the residue hydrol-yzed: to DL -threonine:with -hydrobromic acid;

We have found that am-ination and hydrolysis of dl-d-halO18-21KOXY-Il-bl1t3li0 acid amides prepared from the acid which normally results in the formation of DL-allothreonine rather than the free acid itself, results in inversion of the racemate and recovery of the desired DL-threonine.

The following examples are presented to show how the process of the present invention can be carried out but it is understood that these examples are given primarily by way of illustration and not of limitation.

Example 1 dl-a-Bromo--methoxy-n-butyric acid melting point 62-63 C. was prepared as described by West, Krummel, and Carter, J. Biol. Chem., 122, 605 (1938). A sample of this acid on amination followed by hydrolysis exactly as below gave only atrace of DL-threonine (bioassay). 29.55 grams (0.15 mol) of the dl-a-bromo-p-methoxy-nbutyric acid was dissolved in 150 cc. of benzene and 2 drops of pyridine. To this reaction mixture was added 13.5 cc. of thionyl chloride and the mixture was heated at reflux temperature for 1 hours. The hydrogen chloride and sulfur dioxide formed during the reaction were removed with 50 cc. of benzene by distillation of the mixture under reduced pressure. The residue was then diluted with an additional 100 cc. of benzene.

This benzene solution of dl-a-bromo-B-methoxy-n-butyric acid chloride was cooled in an ice bath and was added dropwise with simultaneous stirring to an ice-cooled solution of 32.5 cc. (0.33 mol) of piperidine in 100 cc. of benzene. The addition was carried out at 4-5 C. and required 1 hours. After removing the ice-bath, the reaction mixture was stirred for an additional half hour before filtering off the piperidine hydrochloride. The filtrate was extracted 3 times with 50 cc. of water and then concentrated under reduced pressure to constant weight 35.1 grams (91.2% of theory). The yellow oil, consisting of crude dl-a-bromo-,6-methoxy-n-butyric acid piperidide crystallized solid on standing for sixteen hours at 5 C. but became sticky on warming to room temperature. Recrystallization of the crude product from a petroleum fraction of boiling point 7'7-115 0. resulted in a 75% yield of dl-a-bromo-pmethoxy-n-butyric acid piperidide which melted at 4143 C. The dl-a-bromo fl-methoxy-n-butyric acid piperidide is soluble in all of the common solvents with the exception of water.

Analysis calculated for CmHraOzNBr;

Found:

A solution of 13.2 grams (0.05 mol) of dl-abromo-fi-methoxy-n-butyric acid piperidide in 60 cc. of methanol and 30 cc. of liquid ammonia was heated at 75 C. for 24 hours in a glass lined bomb. After the ammonia had evaporated from the clear red solution, it was diluted to 200 cc. with methanol and two 5 cc. samples taken for Volhard determination of bromide ion. Determination' showed 98.8% reacted. The reaction mixture was concentrated to dryness under reduced pressure resulting in a residue containing dl-a-amino- 9-methoxy-nbutyric acid piperidide.

To this residue was added 40 cc. of 40% hydrobromic acid and the mixture heated at reflux temperature for hours. to dryness, twice adding water, and reconcentrating to dryness, the residue was dissolved in 40 cc. of water and made alkaline to phenolphthalein with concentrated ammonium hydroxids. The piperidinewas extracted with ether.

After concentrating The aqueous layer was made acid to Congo paper with concentrated hydrochloric acid, treated with activated charcoal and diluted to 100 cc. A 10 cc. sample was removed for bioassay. This sample, neutralized and diluted to 50 cc. with water was found to contain 7.2 mg. of DL-threonine per cc. or 63.7% DL-threonine based on a-blOInO-B- methoxy-n-butyric acid piperidide used. The bioassay method used for determining the DL- threonine content is the method of J. L. Stokes and M. Gunness, published in J. Bact. 52, p. 195 (Aug. 1946).

Isolation of DL-threonine was accomplished by concentrating the remaining cc. of the solution to dryness under reduced pressure. The organic material was extracted from the residual salt using three 25 cc. portions of boiling isopropanol. The isopropanol solution was cooled and a small amount of additional inorganic precipitate was removed by filtration. To the filtrate was added with stirring and scratching 7.8 cc. of aniline and the solution was shaken for sixteen hours. The white precipitate of crude DL-threonine was collected, washed with isopropanol and ether, and finally dried. Recrystallization of the crude DL-threonine from water and alcohol resulted in analytically pure DL- threonine in an overall yield of 58% based on the dl-a-bromo-p-methoxy-n-butyric acid piperidide used. This product was DL-threonine by bioassay.

Analysis calculated for C4H9O3Nt C, 40.33; H, 7.62; N, 11.76

Found:

C, 40.03; H, 7.70; N, 11.96

Example 2 The dl-a-bromo-,B-methoxy-n-butyric acid chloride was prepared as described in Example 1 from 29.6 grams of dl-a-bromo-c-methoxy-nbutyric acid (melting point 62-63 C.). The acid chloride was dissolved in 225 cc. of benzene and cooled in an ice ba h. The solution was then added dropwise with stirring to an ice-cooled solution of 27.6 cc. of aniline in 100 cc. of benzene. The addition was made at 4-5 C. and required one hour. After removing the ice-bath, the reaction mixture was stirred an additional hour and then concentrated to dryness under reduced pressure. The residue was extracted with water leaving 37.7 g. (92.3% of theory) of crude dl a bromo -;3- methoxy -nbutyranilide having a melting point of 102-5 C. Recrystallization of this crude product from a petroleum fraction of boiling point 85-100 C. resulted in rosettes of needles having a melting point of 106-107 C. dl-a-Bromo-e-methoxy-n-butyranilide is readily soluble in methanol, ethanol, and ethyl acetate, moderately soluble in benzene and in hot xylene or petroleum ether; very slightly soluble in water.

Analysis calculated for C11H14O2NB12 Found:

A solution of 13.6 grams (0.05 mole) of dia-bromo45-Inethoxy-n-butyranilide in 60 cc. of methanol and 30 cc. of liquid ammonia was heated at 100 C. for 24 hours in a bomb. Volhard determination showed 100% reacted. The solution was concentrated to dryness in vacuo resulting in a residue containing dl-a-amino-{lmethoxy-n-butyranilide.

eraser-gets 1 {The hydrolyzed solution was concentrated: to

dryness in vacuo and theresiduetwice-dissolved in water and reconcentrated to'dryness. The

*residue was then dissolved in water; treated with carbon, filtered andassayed. There'was found a 46.0% :yield ofaDL-threonine based on dl-abromo-[i-methoxy-n-butyramide used.

Isolation of DL-threonine was accomplished as described in Example l'and resulted in a 47.2%...yield of DL-threonineealloethreonine which assayed 72 DL-threonine.

. Analysis calculated for C4H9O3NI 2 f: 68 DL-threonine :(43.5 of: theory) The yield of recrystallizedrproductlwas 55.2% 'o.t..theory;and

ioa'ssay :showetlzftherlmixtureutosb'e, 72 Va-13L- threonine:i(39;8 ofitheory); anctztheqiremainder a .JDL aIIQthreQnine.

. :Analysis calculated 2 for. .C4H9Q3N:

-.-.:Found:

--Alternatively 'a-mixture' of dd-grams of dl-a- "iororno-fl-methoxy-n butyranilide and 13.4 of liquid ammonia was-heated at 50for 39'hou'rs in a bomb. Hydrolysis" of "the "residueby 'refiuxing *"for' 2hours with cc. of 40 %"hydrogen bromide gave 'a solution which was shown bioassay to 'contain"DIJ-threonine in 24.3% "yield.

: Example 3 A 500} cc-.-' benzene -"solution of -cll--ti-brtnno- 9- I niethox-y-n-butyric acid'chloride was prepared as described in. Example 1 froni 39.4 grams of d1- c-b'romo. fl InethoXyn=--' butyricacidimelting point 62-63" C.).- This solutionwa's--coled= to 5 C; in-an -ice b'ath and-*dry -a'mmonia'r passed "into-themixtUre maintaining the-temperature between 5 6 C. When tl'ierewvas-no-inore=lieat N of reaction (approximately- 451m meager-1ammonia inflow was stopped and the sl-urrywas 'stirredfor 20'minutes at 5 Gi and filtered from ammonium chloride and concentrated- --to --dry- -nessi The --c'rude-- residue -of dl d-bro'mo-fimethoxy-n-buty'ramide containing- 'some amm'oniumchloride was extraeted with acetone to remove ammonium chloride; and the-'fi'ltratefconce'ntr-ated to '1 dry'nessi' There was s'eci'ui'ed 37.1 grams- 1946 "/5 of theory) of crudedl-a bromofi-methox'y n-butyramide liavinga melting point of 85- 98" Ci- Recrystallization from -benzene' re suited incrys'tallineplateshaving a-meitmg po'mt of -106''107i 0: dl- 0. Bromo B mthoXy-n rbuWramideis =readi1ys'dluble: in' "-ethanol; -isopropanol, r? and acetone? moderately seiub1ein water .and in -hot 'ethyl acetate or benz'enejand r v very F slightly soluble in ether.

. Analysis. calculated for C5H10Q2NB1: C, 30.03; 11,514; N; 7.15;

Found:

C,=30.48;.H, 5.19; N, 7.34.

methoxy n-butyramide in 60 cc. of rr'ietha'noland cc. of liquid ammonia was heated at 100 C. 3 for- 24- hours in a glass linedbomb$"-"-Volhard determination showed 98 reacted. '--'-Th'e-r'sultring clear, pale orange solution -was concentrated to dryness resulting" ina residue containing dla-amino-5-methoxy-n-butyramide. v

To this residue was added-42 .5. cc0f 40 hyxd-rogen bromide: and the reaotion n'iixture= was thenaheated at refluxtemperature for-i l5- hours-. i

*"ExampZe 4 A 275 cc. benzene solution Of-dl-a-blOIIlO-filllethOXY-IP-blltYl'iO- acid chloride was. prepared as-described in Example 1 from dl-a-bIOIIlO-flmethoxy-n butyric acid (melting point 62-63 C.). This solutionwas cooled. in an ice bathand .then added dropwise Withagitation to an icecooled solution of 19.9 grams of dimethylarnine (anhydrous) in 125 cc. of benzene. The addition was carriedmut at a temperature of 3-5? G. and required about 1 hour. The ice bath was re moved and the reaction mixture was stirred for an additional /3.}10111: 'The'precipitated dimethylamine hydrochloride -was filtered oil and the filtrate was concentrated under reduced pressure w to an :oi'ange oil. There. was secured 41a!) iigr'ams material was distilled at 6 to 7 mm..:pressure diin'ethyl-a-brcn'io e methoxym butyramide andresulted in a main fractionhaving atboiling point of 101 C. and n 2= 1 .4915.

Analysis calculated for-CwHuOzNBr:

C, 37.51; H,-6.3O

Found:

A solution of 11.2 grams (0.05 mole) of dlN .N-

cc. of methanol and 30 cc. of liquid ammonia washe'ated at"100 C; for 24' hours ma glass-lined bomb. Volhard determination showed 100% reacted. .The reaction inixturewas concentrated to-Qdryness resulting in a residue containing dl- .'N,N-dimethyl-M'amino-pmethoxy-nbutyramide.

To-this residue was added 40 cc. of'40% hydrobi'oinic 'acid' and thereactionmiritureheated to refiuxtemperature for 12 hours. 'Dimethylamine was 'removeolby theisame "method as described inEXarnple lfor the'removal Qf piperidineY The "flsolutionwas then subjected to bioassay and-the yield of 7 DL*-threonine found. to. be 50.5%. The

recrystallized product on bioassay showed-the mixture to be 92% DL-threonine.

---.:; Analysis: :calculatedior 'fiiHaosN .Eound:

C; 450.25; H;l7.83

. Example 5 A rnixture of -dl:m-'bron1o-B-methoxy-n-butyric The dl-- aebr'omo p methoxy-h butyric ama chloride was reacted with aniline in the same manner as Example i.

A solution of 6.8 grams of this dl-a-loromo-6 methoxy-n-butyranilide in 30 cc. of methanol and cc. of liquid ammonia was heated at 75 C. for 24 hours in a bomb. The solution was concentrated to dryness resulting in a residue containing dl-a-a-mino-pmethoxy-nbutyranilide. To this residue was added 42.5 cc. of 49% hydrogen bromide. The reaction mixture was heated at reflux temperature for 14 hours. Bioassay showed a 39% yield of DL-threonine.

For comparison a dl-a-bromo-c-methoxy-nbutyric acid mixture similar to the above starting material was aminated directly by the method of Carter et al. (Organic Syntheses 20, 101 (1940)). The amination mixture was concentrated to dryness in vacuo and hydrolyzed by refluxing for 2 hours with 40% hydrogen bromide. Bioassay showed a 30% yield of DL-threonine.

The above description and examples are intended to be illustrative only. Any modifications of, or variations therefrom, which conform to the spirit of the invention, are intended to be included within the scope of the claims.

We claim:

1. A compound having the structure of R is alkyl, X is halogen, R is selected from the class consisting of NH2, NH-aryl, N(alkyl)2 and secondary N-heterocyclic groups. p

2. dl-a-Bromo-{3-methoxy-n-butyric acid piperidide having a melting point of ll-43 C.

3. dl-a-Bromo-,c-methoxyn-butyric acid anilide having a melting point of MiG-107 C.

4. dl-a-Bromo-5-methoxy-n-butyramide having a melting point of 106-107 C.

5. dl-a-Bromo p-methoxy-(N,N- dimethyl) -nbutyramide having a boiling point of 101-104 C./6-'7 mm. pressure.

6. The process of preparing DL-threonine comprising the steps of reacting a racemate containing dl-a-halo-B-alkoxy-n-butyric acid which normally yields DL-allothreonine on amination and hydrolysis, with a halogenating agent in an organic solvent medium to form dl-a-halo-p-ab koxy-n-butyric acid halide, reacting the latter mixture with a compound selected from the group consisting of ammonia, primary and secondary amines, recovering the corresponding dla-halo-,B-alkoxy-n-butyric acid amido compound thus formed, aminating the latter compound with a liquid selected from the group consisting of liquid ammonia and a mixture of ammoniaand a lower aliphatic alcohol, concentrating the reaction mixture to dryness, hydrolyzing the residue and recovering DL-threonine.

7. The rocess of preparing DL-threonine comprising the steps of reacting a r-acemate containing dl-a-halo-fi-alkoXy-n-butyric acid which normally yields DL-allothreonine on amination and hydrolysis, with thionyl halide in an organic solvent medium to form dl-a-halo-e-alkoxy-nbutyric acid halide, reacting the latter solution with piperidine, recovering a-halo-fl-alkoxy-nbutyric acid piperidide, aminating the latter com.-

pound with a liquid selected from the group consisting of liquid ammonia and a mixture of ammonia and a lower aliphatic alcohol, concentrating the reaction mixture to dryness, hydrolyzing the residue and recovering DL-threonine.

8. The process of preparing DL-threonine comprising the steps of reacting a racemate containing dl-a-halo-fi-alkoxy-n-butyric acid which normally yields DL-allothreonine on amination and hydrolysis, with thionyl halide in an organic solvent medium to form dl-a-halo-p-alkoxy-nbutyric acid halide, reacting the latter solution with aniline, recovering dl-c-halo-p-alkoxy-nbutyric acid anilide, aminating the latter compound with a liquid selected from the group consisting of liquid ammonia and a mixture of ammonia and a lower aliphatic alcohol, concentrating the reaction mixture to dryness, hydrolyzing the residue and recovering DL-threonine.

9. The process of preparing DL-threonine comprising the steps of reacting a racemate containing dl-a-ha1o-,8-alkoXy-n-butyric acid which normally yields DL-allothreonine on amination and hydrolysis, with thionyl halide in an organic solvent medium to form dl-a-halo-pall oxy-nbutyric acid halide, reacting the latter solution with ammonia, recovering dl-ahalo-fi-alkoxy-nbutyramide, aminating the latter compound with a liquid selected from the group consisting of liquid ammonia and a mixture of ammonia and a lower aliphatic alcohol, concentrating the reaction mixture to dryness, hydrolyzing the residue and recovering DL-threonine.

10. The process of preparing DL-threonine comprising the steps of reacting a racemate containing dl-whale-{i-alkoxy-n-butyric acid which normally yields DL-allothreonine on amination and hydrolysis, with thionyl halide in an organic solvent medium to form dlahalo-,8-alkoxy-nbutyric acid halide, reacting the latter solution with dimethylamine, recovering dl-ahalo-- alkoxy-(N,N-dimethyl) -n-butyramide, aminating the latter compound with a liquid selected from the group consisting of liquid ammonia and a mixture of ammonia and a lower aliphatic alcohol, concentrating the reaction mixture to dryness, hydrolyzing the residue and recovering DL- threonine.

11. The process of preparing DL-threonine comprising reacting dl-a-bromo-fi-methoxy-nbutyric acid having a melting point of 62-63 C. with thionyl chloride in a benzene medium to form dl-a-bromo-p-methoxy-n-butyric acid chloride reacting the latter solution with a benzene solution of piperidine, recovering dl-a-bromo-flmethoxy-n-butyric acid piperidide, aminating the latter compound with liquid ammonia, concentrating the reaction mixture to dryness, hydrolyzing the residue and recovering DL-threonine.

12. In the process of preparing DL-threonine the steps comprising aminating dl-a-blOInO-fimethoxy-n-butyric acid piperidide having a melting point of ll-43 C. with a liquid, selected from the group consisting of liquid ammonia, and a mixture of ammonia and a lower aliphatic alcohol, hydrolyzing the resulting (il-a-fil'l'llIlO-fimethoxy-n-butyric acid piperidide and isolating DL-threonine.

13. In the process of preparing DL-threonine the steps comprising aminating d1-a-bI'0lnO-B- methoxy-n-butyric acid anilide having a melting point of 106-107 C. with a liquid, selected from the group consisting of liquid ammonia, and a mixture of ammonia and a lower aliphatic alcohol, hydrolyzing the resulting dl-a-amino-B- methoxy-n-butyric acid anilide and isolating DL- threonine.

14. In the process of preparing DL-threonine the steps comprising aminating dl-a-bI'OIIlO-fimethoxy-n-butyramide having a melting point of 9 106-107 C. with a liquid, selected from the group consisting of liquid ammonia, and a mixture of ammonia and a lower aliphatic alcohol, hydrolyzing the resulting dl-a-amino-fi-methoxy-nbutyramide and isolating DL-threonine.

15. In the process of preparing DL-threonine the steps comprising aminating dl-a-bI'OlllO-B- methoxy (N,N dimethyl) n butyramide having a boiling point of 101104 C./6-'7 mm. pressure with a liquid, selected from the group consisting of liquid ammonia, and a mixture of ammonia and a lower aliphatic alcohol, hydrolyzing the resulting dl-a-amino-p-methoxy- (N,N-dimethyl) -nbutyramide and isolating DL- threonine.

16. In the process for preparing DL-threonine from dl-a-halo-,8alkoxy-n-butyric acid involving converting the a-haloto an a-amino radical and hydrolyzing the 18-alkoxy to a B-hydroxy radical, the improved procedure that comprises selecting a racemate containing dl-e-halo-B- alkoxy-n-butyric acid which normally yields DL- allothreonine on amination and hydrolysis, reacting said dl-a-halo-fi-alkoxy-n-butyric acid with a halogenating agent in an organic solvent medium to form dlahalo- 3-a1koxy-n-butyric acid halide, reacting the latter solution with a compound selected from the group consisting of ammonia, primary and secondary amines and recovering the corresponding dl-a-halo-p-alkoxyn-butyric acid amido compound.

17. In the process for preparing DL-threonine from dl-a-halo-p-alkoxy-n-butyric acid involvin converting the a-halo to an a-amino radical, and hydrolyzing the c-alkoxy to a ,8-hydroxy radical, the improved procedure that comprises selecting a racemate containing dl-a-halo-fialkoxy-n-butyric acid which normally yields DL- allothreonine on amination and hydrolysis, reacting said dl-a-halo-B-a1koxy-n-butyric acid with thionyl halide in an organic solvent medium to form dl-a-halo- 8-alkoxy-n-butyric acid halide, reacting the latter solution with a compound selected from the group consisting of ammonia, primary and secondary amines and recovering the corresponding d1-a-halo-p-alkoxy-n-butyric acid amido compound.

18. In the process for preparing DL-threonine from dl-a-bromo-fi-methoxy-n-butyric acid involving converting the a-bIOIIlO- to an a-amino radical, and hydrolyzing the {3-methoxy to a p-hydroxy radical, the improved procedure that comprises reacting dl-a-blOIllO-B-I'IlthOXY-llbutyric acid having a melting point of 62-63 C. with thionyl chloride in a benzene medium to form dl a bromo 5 methoxy n butyric acid chloride, reacting the latter mixture with piperidine and recovering dl-a-bromo-p-methoxy-n-butyric acid piperidide having a melting point of 4143 C.

19. In the process for preparing DL-threonine from dl-a-bromo-,8-methoxy-n-butyric acid involving converting the a-bromo to an a-amino radical, and hydrolyzing the p-methoxy to a B-hydroxy radical, the improved procedure that comprises reacting dla-bromo-fi-methoxy-nbutyric acid having a melting point of 62-63 C. with thionyl chloride in a benzene medium to form d1 a bromo B methoxy n butyric acid chloride, reacting the latter mixture with aniline, and recovering dl-a-bromo-B-methoxyn-butyric acid anilide having a melting point of 106-10'7 C.

20. In the process for preparing DL-threonine from dle-bromo-,6-methoxy-n-butyric acid involving converting the a-bromoto an a-amino radical and hydrolyzing the ,B-methoxy to a p-hydroxy radical, the improved procedure that comprise reacting dl-a-bromo-;3-methoXy-n-butyric acid having a melting point of 62-63 C. with thionyl chloride in a benzene medium to form dl-a-bromo-/3-methoxy-n-butyric acid chloride reacting the latter mixture With ammonia, and recovering dl-a-bromo-,B-methoxy-n-butyramide having a melting point of 106-107 C.

21, In the process for preparing DL-threonine from dl-a-bromo- 8-methoxy-n-butyric acid involving converting the a-bromo to an amino radical and hydrolyzing the 5-methoxy to a 5-hydroxy radical, the improved procedure that com-' prise reacting dl-a-bromo-;i-methoxy-n-butyric acid having a melting point of 62-63 C. with thionyl chloride in a benzene medium to form dl-a-bromo-,8-methoxy-n-butyric acid chloride, reacting the latter mixture with dimethylamine and recovering dl-a-bromo-fi-methoxy-(N,N-dimethyl) -n-butyramide having a boiling point of 101-104 C./67 mm. pressure.

KARL PFISTER, III.

CHARLES A. ROBINSON.

MAX TISHLER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,446,192 Pfister et al. Aug. 3, 1948 2,447,361 Peck et al. Aug. 17, 1948 OTHER REFERENCES Jacobs et al., Beilstein (Handbuch, 4th Ed., 1st Sup.), vol. 4, p. 352 (1929).

Burch, J. Chem. Soc., vol. 1930, pp. 310-312.

West et al., J. Biol. Chem., vol. 122, p. 605 (1938).

Carter et al., Organic Syntheses, vol. 20, p. 101 (1940).

Wood et al., J. Biol. Chem., vol. 134, pp. 413- 416 (1940).

Von Braun et al., Beilstein (Handbuch, 4th Ed., 2nd Sup), vol 4, p. 783 (1942). 

1. A COMPOUND HAVING THE STRUCTURE OF
 6. THE PROCESS OF PREPARING DL-THREONINE COMPRISING THE STEPS OF REACTING A RACEMATE CONTAININD DL-A-HALO-B-ALKOXY-N-BUTYRIC ACID WHICH NORMALLY YIELDS DL-ALLOTHREONINE ON AMINATION AND HYDROLYSIS, WITH A HALOGENATING AGENT IN AN ORGANIC SOLVENT MEDIUM TO FORM D1-AHALO-B-ALKOXY-N-BUTYRIC ACID HALIDE, REACTING THE LATTER MIXTURE WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF AMMONIA, PRIMARY AND SECONDARY AMINES, RECOVERING THE CORRESPONDING D1A-HALO-B-ALKOXY-N-BUTYRIC ACID AMIDO COMPOUND THUS FORMED, AMINATING THE LATTER COMPOUND WITH A LIQUID SELECTED FROM THE GROUP CONSISTING OF LIQUID AMMONIA AND A MIXTURE OF AMMONIA AND A LOWER ALIPHATIC ALCOHOL, CONCENTRATING THE REACTION MIXTURE TO DRYNESS, HYDROLYZING THE RESIDUE AND RECOVERING DL-THREONINE. 